This project will examine the relationship between the human VH germline, the antibody repertoire, and autoimmune disease. Our goal is to understand the influence on autoimmunity of coding region heterogeneity of germline VH genes. It is likely that variation in the antibody repertoire influences the manifestation of autoimmune disease. The experiments outlined in this proposal will test the hypothesis that variation in the expressed repertoire is in part a product of polymorphic differences in VH genes. The expressed repertoire has developmental and adult phases which will be independently examined and compared. The first aim will establish the characteristics of the developmentally expressed VH genes. The second aim will establish the characteristics of the adult repertoire against which the developmental repertoire is to be compared. The third aim will determine the extent to which the developmental and adult repertoires employ distinct genes and the extent to which germline encoded autoantibodies derive preferentially from the developmental repertoire. The fourth aim will assess the extent to which particular VH elements appear in the adult repertoire in the context of differing genetic backgrounds. A refinement of the technology of using short oligonucleotide probes on genomic DNA digests has provided a powerful approach to identifying individual genes it has become possible dissect and map the locus in great detail. The information gained form this project should make it possible in the context of the overall program project to approach questions regarding the importance of specific immunoglobulin sequences in disease resistance or susceptibility.